Case Report: Perioperative application of trastuzumab deruxtecan in HER2 exon 20 mutation-positive non-small cell lung cancer

Background Lung adenocarcinoma with HER2 exon 20 insertions represents a rare subset of non-small cell lung cancer (NSCLC) associated with aggressive behavior and limited treatment options. Case description This case report highlights the first perioperative use of trastuzumab deruxtecan (T-DXd) in a 51-year-old male diagnosed with HER2 exon 20-mutant pulmonary adenocarcinoma (T1cN2M0). At diagnosis, a 2.2 × 2.8 × 1.5 cm lesion in the right upper lobe showed moderately elevated metabolic activity (SUVmax 4.20). An initial cycle of chemoimmunotherapy failed to achieve significant tumor reduction. Genetic testing revealed HER2 exon 20 and TP53 mutations, prompting a shift to two cycles of neoadjuvant T-DXd, which reduced the tumor size to 2.0 × 2.4 × 1.0 cm with substantially lowered metabolic activity (SUVmax 1.38). The lesion was successfully resected, confirming invasive adenocarcinoma with 30% viable tumor tissue and 70% stromal tissue, indicating partial tumor suppression. The patient received 14 cycles of adjuvant T-DXd, achieving 28 months of sustained remission. Molecular residual disease (MRD) monitoring through circulating tumor DNA (ctDNA) was conducted throughout adjuvant therapy, initially showing no detectable disease. However, ctDNA positivity with HER2 and TP53 mutations emerged later, prompting timely treatment adjustments. Conclusion This case shows that perioperative treatment with T-DXd could induce tumor regression and sustain remission, while MRD monitoring enables early detection of molecular progression. These findings emphasize the potential of combining T-DXd and MRD monitoring to tailor treatment to improve outcomes in HER2 -mutant NSCLC.